Yesterday, the company reported that the PRO-814 Phase 3 study, comparing maintenance treatment with Probuphine to treatment with a daily dosed sublingual buprenorphine/naloxone tablet, met the FDA’s pre-specified primary endpoint of non-inferiority, as well as all secondary efficacy endpoints.

Buprenorphine, the active ingredient in the Probuphine implant, is the standard of care for the treatment of opioid dependence, replacing methadone. It is currently available as daily dosed sublingual tablets and film formulations, with estimated 2013 sales of $1.5-billion for the oral formulation in the U.S.

“Our implant has shown that it can provide around-the-clock drug delivery and maintain a stable level of drug in the blood for six months, with clinically meaningful benefits for patients,” Sunil Bhonsle, president, says in an interview with BioTuesdays.com.

“We have demonstrated not only non-inferiority against the standard of care in this trial, but also previously demonstrated effectiveness of Probuphine in placebo controlled studies” he adds.

Mr. Bhonsle also contends that the therapeutic benefit demonstrated by Probuphine would allow the company to use its ProNeura technology with other drugs in other disease settings to create a deeper pipeline.

The objective of the Phase 3 study was to show non-inferiority between the Probuphine and buprenorphine/naloxone treatment groups. Subjects in the trial were randomized to receive either four Probuphine implants plus daily placebo sublingual tablets, or four placebo implants plus daily sublingual buprenorphine/naloxone tablets for a treatment period of six months.

Response rates were 96.4% for the Probuphine arm and 87.6% for the sublingual buprenorphine arm. The two-sided 95% confidence interval of the treatment difference between the two arms was well above the minimum pre-defined successful margin for non-inferiority.

Randomized, double blind and double dummy design. Primary efficacy endpoint based on a non-inferioritycomparison of ‘responders’ following six months of treatment with either a dose of four Probuphine implants ortreatment with 8 mg or less of an approved daily dosed sublingual tablet formulation of buprenorphine. Patientenrollment completed in November 2014 – two months ahead of schedule.

The Pro-814 study was conducted by Titan’s U.S. and Canadian commercialization and development partner, Braeburn Pharmaceuticals, and was designed in consultation with the FDA to address a key question about the clinical benefit of Probuphine in a Complete Response Letter issued in April 2013.

Mr. Bhonsle says Titan and Braeburn intend to resubmit their NDA for Probuphine in the second half this year and potentially secure approval for the implant in the first half of 2016.

The NDA is still considered to be under priority review by the FDA based on Probuphine’s potential for decreased abuse, diversion, overdose, and pediatric exposure risk.

Titan has completed seven clinical trials with Probuphine, including two open label long-term treatment safety studies and two earlier Phase 3 safety and efficacy studies showing clinical and statistical superiority over placebo and non-inferiority to Suboxone, which was published in the Journal of American Medical Association and the journal, Addiction.

Dr. Kate Glassman-Beebe, EVP and chief development officer, points out that earlier Phase 3 trials enrolled opiate addicted patients who had not been treated in at least the previous 90 days with buprenorphine or other medications. The FDA had requested another trial to demonstrate that Probuphine was effective in a population of clinically stable, maintenance patients.

Kate Glassman-Beebe

“This group had to have been stable on buprenorphine for at least three months before coming into the study and also had to demonstrate to their clinicians that they had started a recovery process and had stability in their lives in terms of social function and compliance to treatment,” she adds.

In addition, Dr. Glassman-Beebe says the PRO-814 trial once again demonstrated that the Probuphine implant can be safely inserted under the skin and safely removed.

According to recent estimates, there are 2.2 million people with opioid dependence in the U.S. Approximately 20% of this population is addicted to illicit opioids, such as heroin, and the other 80% to prescription opioids, such as oxycodone, hydrocodone, methadone, hydromorphone and codeine.

The Drug Addiction Treatment Act of 2000 allows medical office-based treatment of opioid dependence and has greatly expanded patient access to medication-assisted treatments. An estimated 1.2 million people in the U.S. sought treatment for opioid dependence in 2011.

“As a subdermal implant, Probuphine could minimize the risk of abuse, and, with continuous drug delivery providing around-the-clock medication for six months, Probuphine could become a particularly valuable new tool in the maintenance treatment of opioid addiction,” Dr. Walter Ling, a clinical investigator in the study and founding director of the Integrated Substance Abuse Programs at the David Geffen School of Medicine at University of California, Los Angeles, said in a statement.

Dr. Genie Bailey, another clinical investigator in the study and clinical associate professor of psychiatry and human behavior at the Warren Alpert Medical School at Brown University, said opioid addiction, from heroin to prescription painkillers, remains at crisis levels in the U.S.

“While we have advanced our understanding of the science of addiction, there is no question that significant unmet medical need remains as patients and their families continue to struggle with this disease,” she said.

Epidemic of Opioid Dependence

“Probuphine holds great promise, not just because of its potential for treating opioid addition, but also because, as a six-month implant, it allows patients to resume their lives without the constant reminder of their addiction,” Dr. Bailey added.

Titan’s Dr. Glassman-Beebe says the company will be requesting new meetings with health authorities outside the U.S. for guidance on the path forward for regulatory approval of Probuphine.

At the same time, Titan plans to meet with companies outside the U.S. that might be interested in commercializing Probuphine. “We have held discussions with several companies and believe talks will progress now that we have strong Phase 3 results in hand and hope to get regulatory guidance soon,” she suggests.

Mr. Bhonsle says that with the amount of safety and efficacy data already obtained, “we hope European health authorities will see the benefits of Probuphine so that existing data will be sufficient for a regulatory submission.”

In addition to Europe, Titan also hopes to advance Probuphine in Asia and Australia. “We will be looking at countries where buprenorphine treatment is already in place,” he adds.

Beyond opioid addiction, Titan is using its ProNeura drug delivery technology to develop an implant with ropinirole, a generic dopamine agonist, as a treatment for Parkinson’s disease.

Mr. Bhonsle says Titan is attempting to show that long-term, steady administration of the drug has certain clinical benefits, specifically controlling Parkinson’s symptoms without triggering dyskinesias.

Research in the literature already has established that the best way to provide Parkinson’s medications is at a steady level in the blood, without the side effects resulting from daily fluctuations with oral dosing.

Titan is currently conducting non-clinical studies with ropinirole in order to submit an IND and begin a proof-of-concept clinical study in the second half of 2016. “ProNeura for Parkinson’s has the potential to significantly enhance Titan’s value,” Mr. Bhonsle adds.